The human DF3/MUC1 transmembrane protein is aberrantly expressed at high levels on the surface of multiple myeloma cells. Certain insights about the function of MUC1 have been derived from the finding that the cytoplasmic tail of MUC1 interacts with b-catenin, a signaling protein associated with the development of diverse human tumors. The interaction between MUC1 and b-catenin is regulated by receptor tyrosine kinases, members of the c-Src family and glycogen synthase kinase 3b (GSK3b). In multiple myeloma cells, stimulation with IL-7 induces interaction of MUC1 and the Lyn tyrosine kinase. Lyn phosphorylates the MUC1 cytoplasmic domain and increases binding of MUC1 to beta-catenin. The functional significance of this interaction is supported by the finding that MUC1 regulates nuclear targeting of beta-catenin. Our hypothesis is that MUC1 expression contributes to the malignant phenotype of multiple myeloma cells and that MUC1 represents a target for myeloma therapy. The novel isocoumarin 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) proprionic acid (NM-3) has recently entered Phase I trials as an orally bioavailable inhibitor of angiogenesis. In in vitro studies of multiple myeloma cells, NM-3 disrupts binding of MUC1 to b-catenin and, as a later event, downregulates MUC1 expression. NM-3 also induces killing of multiple myeloma cells at concentrations that have been achieved clinically without toxicity. The results further demonstrate that NM-3 potentiates the effects of standard agents, such as dexamethasone, in inducing multiple myeloma cell death. We propose to define the clinical activity of NM-3 in the treatment of multiple myeloma as a single agent and in combination with agents used in the treatment of this disease. Our hypothesis is that NM-3 will induce multiple myeloma cell death, at least in part, by disrupting MUC1 signaling. This hypothesis will be addressed by studying the effects of NM-3 on MUC1 function in multiple myeloma cells in vitro and on MUC1 expression in vivo. The Specific Aims are: 1) To define the functional significance of MUC1 expression in multiple myeloma cells; 2) To assess the role of MUC1 as a receptor in multiple myeloma cells; 3) To define the effects of NM-3 on MUC1 signaling and induction of lethality in multiple myeloma cells; and 4) To perform a Phase II pharmacokinetic/pharmacodynamic trials of NM-3 alone and in combination with standard agents for the treatment of multiple myeloma.